Immunological mechanisms of intravesical chitosan/interleukin-12 immunotherapy against murine bladder cancer.
Immunological mechanisms of intravesical chitosan/interleukin-12 immunotherapy against murine bladder cancer.
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DOI：
10.1080/2162402x.2016.1259050
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发表时间：
2017
期刊：
影响因子：
7.2
通讯作者：
Zaharoff DA
中科院分区：
文献类型：
--
作者：
Smith SG;Baltz JL;Koppolu BP;Ravindranathan S;Nguyen K;Zaharoff DA
对于能够诱导持久的抗肿瘤免疫的膀胱癌免疫疗法，有一个迫切的临床需求尚未得到满足。我们已经证明，使用白介素12和生物聚合物壳聚糖的简单联合配方的四种膀胱内治疗不仅可以摧毁原位膀胱肿瘤，而且还可以促进有效的持久的全身免疫反应，这一点通过肿瘤特异性的体外杀伤试验、对再攻击的完全保护和对远处未治疗的肿瘤的异常抗肿瘤反应来证明。这项研究调查了这些结果背后的免疫学动力学。我们通过耗竭研究表明，CD8+T细胞是初始肿瘤排斥所必需的，但CD4+T细胞保护免受再攻击。我们还表明，即使是一次膀胱内治疗也可以消除50%的小鼠的肿瘤，分别有6/9和7/8的小鼠在三次或四次治疗后消除肿瘤。然后，我们进行了免疫表型研究，以分析每次治疗后肿瘤自身以及次级淋巴器官中免疫细胞群的变化。这些研究表明，最初的巨噬细胞和粒细胞的渗透，随之而来的是CD4+和CD8+效应记忆细胞增加。这与外周淋巴结中调节性T细胞水平的降低以及膀胱中髓系来源的抑制细胞的渗透减少有关。综上所述，这些数据表明，适当提供的基于白细胞介素12的疗法能够在肿瘤本身以及整个身体内进行适应性免疫，并加强了将壳聚糖/白细胞介素12作为膀胱癌膀胱内治疗的临床翻译的理由。
There is a critical unmet clinical need for bladder cancer immunotherapies capable of inducing durable antitumor immunity. We have shown that four intravesical treatments with a simple co-formulation of interleukin-12 and the biopolymer chitosan not only destroy orthotopic bladder tumors, but also promote a potent long-lasting systemic immune response as evidenced through tumor-specific in vitro killing assays, complete protection from rechallenge, and abscopal antitumor responses at distant non-treated tumors. This study investigates the immunological kinetics underlying these results. We show through depletion studies that CD8+ T cells are required for initial tumor rejection, but CD4+ T cells protect against rechallenge. We also show that even a single intravesical treatment can eliminate tumors in 50% of mice with 6/9 and 7/8 mice eliminating tumors after three or four treatments respectively. We then performed immunophenotyping studies to analyze shifts in immune cell populations after each treatment within the tumor itself as well as in secondary lymphoid organs. These studies demonstrated an initial infiltration of macrophages and granulocytes followed by increased CD4+ and CD8+ effector-memory cells. This was coupled with a decreased level of regulatory T cells in peripheral lymph nodes as well as decreased myeloid-derived suppressor cell infiltration in the bladder. Taken together, these data demonstrate the ability of properly delivered interleukin-12-based therapies to engage adaptive immunity within the tumor itself as well as throughout the body and strengthen the case for clinical translation of chitosan/interleukin-12 as an intravesical treatment for bladder cancer.